Tumor-infiltrating exhausted CD8(+) T cells dictate reduced survival in premenopausal estrogen receptor–positive breast cancer

CD8(+) tumor-infiltrating lymphocytes (TILs) are associated with improved survival in triple-negative breast cancer (TNBC) yet have no association with survival in estrogen receptor–positive (ER(+)) BC. The basis for these contrasting findings remains elusive. We identified subsets of BC tumors infiltrated by CD8(+) T cells with characteristic features of exhausted T cells (T(EX)). Tumors with abundant CD8(+) T(EX) exhibited a distinct tumor microenvironment marked by amplified interferon-γ signaling–related pathways and higher programmed death ligand 1 expression. Paradoxically, higher levels of tumor-infiltrating CD8(+) T(EX) associated with decreased overall survival of patients with ER(+) BC but not patients with TNBC. Moreover, high tumor expression of a CD8(+) T(EX) signature identified dramatically reduced survival in premenopausal, but not postmenopausal, patients with ER(+) BC. Finally, we demonstrated the value of a tumor T(EX) signature score in identifying high-risk premenopausal ER(+) BC patients among those with intermediate Oncotype DX Breast Recurrence Scores. Our data highlight the complex relationship between CD8(+) TILs, interferon-γ signaling, and ER status in BC patient survival. This work identifies tumor-infiltrating CD8(+) T(EX) as a key feature of reduced survival outcomes in premenopausal patients with early-stage ER(+) BC.